The technical field of this invention is the treatment of active factor deficiency disorders and, in particular, the treatment of diseases and disorders which may be remedied by treatment with active factors, such as neurotransmitters, neuromodulators, hormones, trophic factors, cofactors, and growth factors. All these substances are characterized by the fact they are secreted by "source" cells and produce a specific change in a "target" cell or in the source cell itself.
Deficits in active factors have been implicated in disease with very different phenotypes. For example, lack of neurotransmitter-mediated synaptic contact causes neuropathological symptoms, and can also lead to the ultimate destruction of the neurons involved.
More particularly, paralysis agitans, commonly known as Parkinson's disease, is characterized by a lack of the neurotransmitter, dopamine, within the striatum of the brain, secondary to the destruction of the dopamine secreting cells of the substantia nigra. Affected subjects demonstrate a stooped posture, stiffness and slowness of movement, and rhythmic tremor of limbs, with dementia being often encountered in very advanced stages of the disease.
The direct administration of purified or synthetic dopamine, its precursors, analogs and inhibitors has been studied for therapeutic value in the treatment of Parkinson's disease. These studies have revealed various problems with delivery, stability, dosage, and cytotoxicity of the applied compounds. To date, none of these approaches has demonstrated more than marginal therapeutic value. Brain derived growth factor also may have potential value in the treatment of Parkinson's disease since it has been demonstrated to maintain the viability of striatal neurons in vitro.
Many other deficiency diseases, such as diabetes, myxedema, growth deficiencies and perhaps even Alzheimer's disease, appear to be based in whole or in part on the absence or limited availability of a critical active factor to target cells.
In an attempt to provide a constitutive supply of drugs or other factors to the brain or other organs or tissues at a controlled rate, miniature osmotic pumps have been used. However, limited solubility and stability of certain drugs, as well as reservoir limitations, have restricted the usefulness of this technology. For example, controlled sustained release of dopamine has been attempted by implanting dopamine encapsulated within bioresorbable microcapsules (McRae-Degueurce et al. (1988) Neurosci. Lett. 92:303-309). However, controlled sustained release of a drug from a bioresorbable polymer may rely, e.g., on bulk or surface erosion, which may be due to various hydrolytic events. Erosion often relies on hydrolytic events which increase the likelihood of drug degradation, and complicates establishment of predictable release rates. Other disadvantages associated with pumps and resorbable polymers include finite loading capabilities and the lack of feedback regulation.
The implantation of cells capable of constitutively producing and secreting biologically active factors has also been attempted. Recently, remedial transplantation of neurotransmitter-secreting tissue has been accomplished using the patient's own tissue so as not to elicit an immune response. For example, catecholamine-secreting tissue from the adrenal medulla of patients suffering from Parkinson's disease has been implanted in their striatum with some success. However, this procedure is only used in patients less than 60 years of age, as the adrenal gland of older patients may not contain sufficient dopamine-secreting cells. This restriction limits the usefulness of the procedure as a remedy since the disease most often affects older people.
Other approaches have been attempted to transplant cells into brain tissue even though the brain is considered "immuno-privileged", rejection ultimately occurs with both allografts and xenografts. This problem necessitates the co-administration of immuno-suppressors, the use of which renders their own set of complications and deleterious side-effects.
A number of researchers have proposed the use of microcapsules, i.e., tiny spheres which encapsulate a microscopic droplet of a cell solution, for both therapeutic implantation purposes and large scale production of biological products.
An alternative approach has been macroencapsulation, which typically involves loading cells into hollow fibers and then sealing the extremities. In contrast to microcapsules, macrocapsules offer the advantage of easy retrievability, an important feature in therapeutic implants.
However, there are shortcomings in both the microcapsule and macrocapsule approaches to cell culturing. The viability of encapsulated cells as in vivo implants often fails for as yet undetermined reasons. Even when the cells remain viable, they sometimes secrete their products at lower than therapeutically useful levels.
Therefore, there exists a need for improved therapies for the treatment of active factor deficiency disorders in general and, in particular, a need for therapy devices which can revitalize or replace the functions of dysfunctional areas of the brain or other organs without causing excessive trauma. More specifically, there exists a need for methods of enhancing and/or sustaining the delivery of biologically active factor to a localized region of a subject.
Accordingly, it is an object of the present invention to provide more reliable or more potent, implantable, therapy devices useful for the sustained and controlled delivery of a biologically active factor to a subject, and more particularly, to provide devices which can deliver a biologically active factor, e.g., a neuroactive trophic factor, or growth factor, to a localized region of a tissue or organ in a subject.